Bardet Biedl Syndrome

What is Bardet Biedl Syndrome?

There are 19 genes identified, which involve in Bardet Biedl Syndrome (BBS) development. But ailment in cilia is a most crucial element in developing BBS. The genetic malfunction is associated with cilia the primary component of cellular communication resulting Bardet Biedl Syndrome. In precise, BBS has been categorized as a ciliopathy. There are multiple symptoms appear in BBS, but that are based on which gene is primarily involved¹.

The incidence of Bardet Biedl Syndrome is rare. Georges Bardet and Artur Biedl clinically described BBS in the early 1920s. However, Laurence and Moon first described similar fashion of clinical symptoms in 1866. Previously, it creates confusion that both described ailments may not same or may overlap the symptomatic approach, but later this confusion become over and now the disease is known as Bardet Biedl Syndrome².

Causes

Bardet Biedl syndrome usually resultant of inherited autosomal recessive trait. The trait of genetic abnormal chromosomes receives from the father and the mother. The involve genes get some instruction to synthesize certain proteins.

The abnormal mutation causes a malfunction in protein synthesis and resultant of this cause deficiency. The involved proteins deficiency affects immotile cilia, as proteins participate in the development, upholding, and function of cilia. In Bardet-Biedl syndrome, cell movement hampers and causes immotible cilia play a role in cell movement. The following different identified pathogenic variants responsible for the onset of Bardet-Biedl syndrome³.

Gene Involvement

There is 14 genes first discovered as pathogenic variants associated with Bardet Biedl Syndrome, which include BBS1, BBS2, BBS3 (ARL6), BBS4, BBS5,  BBS6 (MKKS ), BBS7, BBS8 (TTC8 ), BBS9, BBS10, BBS11(TRIM32), BBS12, BBS13(MKS1), and BBS14 (CEP290).

Later additional five genes are discovered as pathogenic variants, which may have a role in Bardet Biedl Syndrome development. The included genes are BBS15 (WDPCP ), BBS16 (SDCCAG8), BBS17 (LZTFL1), BBS18 (BBIP1), and BBS19 (IFT27).

But yet now almost 20% of BBS cases does not possess same genes, which were discovered as a pathogenic variant. Therefore, it is assumed that there is a possibility of other genes involvement in the progression of BBS, which may yet to discover¹.

Symptoms

Rod-cone dystrophy

One of the characteristic features of BBS is exceptional pigmentary retinal dystrophy with the early macular association is termed as rod-cone dystrophy. The resultant of this cause loss of vision, but may not be identified at the early stage of life. The vision impairment at the dim light usually started at age of 7 to 8 years of age.

Other ocular problems

Apart from rod-cone dystrophy, several different ocular problems may arise, which include crossed eyes, irregular, involuntary quick eye movements, cataracts, and glaucoma.

Postaxial polydactyly

In simple language, Postaxial polydactyly means presences of extra finger or toe formation in hand or feet. The position of extra digit usually near the fifth finger or toe, but may present in between second and third finger. The size of the extra digit is smaller than the normal finger or toe.

Obesity

Excessive fat deposition on abdomen and chest causes is more than limbs. This disproportionate fat distribution is also a considerable characteristic feature. Though this symptom is not prominent at the time of birth, but the later stage of life it has been developing.

Learning disabilities

BBS patients usually have mild to moderate learning disabilities due to mental retardation, but in some cases, significant learning problem may arise.

Reproductive abnormalities

Male patients with BBS have hypogonadism,  small sized penis, delayed puberty and cryptorchidism (testes unable to slide down into the scrotum). Females with BBS also have different genitourinary-related problems arise like underdeveloped uterus, fallopian tubes, and ovaries; a divided vagina; incomplete or fully contracted vagina; duplex uterus; watery fluid accumulated in the uterus and vagina; an unusual channel formation between the bladder and the vagina; and lack of the vaginal or urethral orifice. Irregular menstrual cycle often reported with BBS affected females.

Kidney problems

Decreased kidney functionality and resultant of this leads to abnormal accumulation of urine in the kidney, thus inflammation develops in the kidneys and pelvis. Continual problem of this causes renal impairment.

Speech impairment

Children affected with Bardet Biedl Syndrome often have delayed speaking ability and speech impairment. The typical tone of voice with piercing, nasal tone, and poor pronunciation are also found in affected patients.

Behavioral abnormalities

Different behavioral abnormalities are reported in patients with Bardet Biedl Syndrome, such as anxiety, depression, mood swings and OCD (obsessive-compulsive disorder).

Facial abnormalities

Discrete facial features including widely-spaced with deep-set eyes, an even bridge of the nose with nostrils, an extended channel in the middle of the upper lip, and downward-slanting eyelid folds.

Other abnormalities

Other organ-specific abnormalities are the abnormal positioning of internal organs, hearing loss, otitis media, dental abnormalities, hepatic fibrosis, congenital heart malformations, hypertension and metabolic disorder like diabetes mellitus^1,,2,3,4.

Diagnosis

The usual method of detection of Bardet-Biedl Syndrome is based on symptomatic analysis, physical examination and clinical feature observation.

Molecular genetic testing may conduct for confirmatory test

Genotyping is also conducted for excluding the chance of other rare genetic disorders.

Less frequently molecular analysis is performed because of clinical and genetic heterogeneity. But recent days, novel method of next-generation sequencing of molecular analysis has been implemented.

After detection of BBS syndrome, the further different diagnostic analysis is conducted for diagnosing the extent of the ailment. The included assessments are

• Ophthalmological examination, which includes visual fields, visual acuity, and fundoscopy
• Abdominal and pelvic ultrasound to examine internal organs and genitalia.
• Dietary assessment and BMI calculation
• Kidney- urinary tract and bladder (KUB) examination through ultrasonography and renal function assessment through a different blood test.
• Blood pressure monitoring
• ECG and echocardiogram is conducted to check cardiac condition
• Overall Growth evaluation⁵

Management

There is no specific treatment available to treat BBS. The goal of treatment management is to control the symptomatic spreading or restrict further complications.

• Using of low vision aids provides benefits for vision worsening condition. Mobility training also provided for a patient who lost vision.
• Consultation with nephrologists and periodic evaluation of renal function is important to manage kidney problems.
• Obesity-related complications like hyperlipidemia, diabetes etc may require being tackled clinically.
• Measured diet plan, regular exercise, and behavioral therapies may be beneficial to control obesity.
• Surgical removal of extra digits may helpful to improve functionality and make easy to fit of a footwear.
• Prompt treatment require treating otitis media
• Dental crowding can b management by tooth extraction
• Special education training may require for patient who suffers severe learning difficulty or cognitive impairment
• Speech therapy recommended for patient who has delayed speech or speech impairment^1,3,5

Life Expectancy

Life expectancy is poor in Bardet-Biedl Syndrome in renal failure⁵.

References

1. Elizabeth Forsythe, Philip L; Beales; Bardet-Biedl Syndrome; Initial Posting: July 14, 2003; Last Revision: April 23, 2015; https://www.ncbi.nlm.nih.gov/books/NBK1363/
2. Elizabeth Forsythe, Philip L Beales; Bardet–Biedl syndrome; European Journal of Human Genetics (2013) 21, 8–13; doi:10.1038/ejhg.2012.115; published online 20 June 2012; http://www.nature.com/ejhg/journal/v21/n1/full/ejhg2012115a.html
3. P L Beales, N Elcioglu, A S Woolf, D Parker, F A Flinter; New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey; J Med Genet 1999;36:437-446 doi:10.1136/jmg.36.6.437; http://jmg.bmj.com/content/36/6/437.long
4. Bardet-Biedl syndrome; Genetic Home Reference; https://ghr.nlm.nih.gov/condition/bardet-biedl-syndrome#diagnosis
5. Dr. Hayley, Dr. Anjum Gandhi; Beales; Bardet-Biedl Syndrome; http://patient.info/in/doctor/bardet-biedl-syndrome